This Medications Development Research Center builds on the strengths and achievements of our existing Center, while developing innovative advances in medications development for opioids, cocaine, marijuana, and one of the (re)emerging drugs of concern, methamphetamine. We have created laboratory models for the initial evaluation of medications and developed procedures for the translation of our laboratory findings to the clinic. The major themes of the Center are: 1) model development, 2) targeted pharmacotherapy, 3) predictors of response, and 4) evaluating medications for emerging problems. The Center consists of 2 Cores and 5 Projects, among which there is considerable synergy and interdependency. Unifying all of the Projects are the Central Administrative Core (Core I) and the Biostatistics, Training and Education Core (Core II). Core I provides administrative and research support including research and nursing staff, clinical services, research facilities, laboratory resources, a centralized and standardized recruitment and screening program, and funding for pilot studies. The Biostatistics component of Core II provides the necessary statistical support for the Center and the Training and Education component of Core II is dedicated to education, training, mentoring in, as evidenced by our successful Substance Abuse Fellowship and extensive education (with our Fellowship program) to medical students, residents, and fellows. Project 1 will evaluate the ability of two glial inhibitors, ibudilast and minocycline, to alter prescription opioid self administration and relapse in humans. Project 2 will assess microglial inhibition for methamphetamine dependence using neuroimaging techniques in non-human primates and humans. Project 3 will employ the brain imaging techniques previously developed in Project 2 to the clinic by combining neuroimaging of dopamine transmission with a randomized clinical trial in cocaine-dependent individuals to evaluate the efficacy of medications that increase synaptic dopamine levels. Similarly, Project 4 will build on previous findings from Project 5 by conducting a randomized clinical trial comparing dronabinol + lofexidine to placebo for the treatment of cannabis dependence. Project 5 will now assess other potential triggers (proximal cues and priming) for marijuana relapse in the laboratory and test medications for each of these triggers. The thematic coherence between the Cores and the Projects is what allows our Center to foster original and creative contributions to the scientific understanding of medications development for drug abuse that is far greater than what could be achieved independently.